tbuckley/cabot-search huggingface dataset:
Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus
Authors: Jon Foss-Skiftesvik, Shaobo Li, Adam Rosenbaum, Christian Munch Hagen, Ulrik Kristoffer Stoltze, Sally Ljungqvist, Ulf Hjalmars, Kjeld Schmiegelow, Libby Morimoto, Adam J de Smith, René Mathiasen, Catherine Metayer, David Hougaard, Beatrice Melin, Kyle M Walsh, Jonas Bybjerg-Grauholm, Anna M Dahlin, Joseph L Wiemels
Journal: Neuro-Oncology (2023)

Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date.Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18 628 genes.Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179-1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (P-value of 8.090e-8).In this population-based genome-wide association study meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.
Hysterectomy, bilateral oophorectomy, and breast cancer risk in a racially diverse prospective cohort study
Authors: Sharonda M Lovett, Dale P Sandler, Katie M O’Brien
Journal: JNCI Journal of the National Cancer Institute (2023)

Gynecologic surgery is hypothesized to reduce risk of breast cancer; however, associations may be modified by subsequent hormone use. Our objective was to examine the association between gynecologic surgery and breast cancer incidence considering the use of hormone therapy.The Sister Study is a prospective cohort of initially breast cancer-free women aged 35-74 years with a sister who had breast cancer. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between gynecologic surgery (no surgery, hysterectomy only, bilateral oophorectomy with or without hysterectomy) and incident breast cancer among 50 701 women.History of gynecologic surgery was common, with 13.8% reporting hysterectomy only and 18.1% reporting bilateral oophorectomy with or without hysterectomy. During follow-up (median = 11.4 years), 3948 cases were diagnosed. Compared with no surgery, bilateral oophorectomy was inversely associated with breast cancer (HR = 0.91, 95% CI = 0.83 to 1.00), and hysterectomy alone was positively associated (HR = 1.12, 95% CI = 1.02 to 1.23). Compared with no surgery and no hormone therapy, bilateral oophorectomy combined with estrogen only therapy (HR = 0.83, 95% CI = 0.74 to 0.94) was inversely associated with breast cancer, while hysterectomy combined with estrogen plus progestin therapy was positively associated with breast cancer (HR = 1.25, 95% CI = 1.01 to 1.55).We observed an inverse association between bilateral oophorectomy and breast cancer risk. The positive association between hysterectomy and breast cancer may be due to concomitant estrogen plus progestin therapy.
Multi-omics Investigation of Freeze Tolerance in the Amur Sleeper, an Aquatic Ectothermic Vertebrate
Authors: Haifeng Jiang, Wenqi Lv, Ying Wang, Yuting Qian, Cheng Wang, Ning Sun, Chengchi Fang, David M Irwin, Xiaoni Gan, Shunping He, Liandong Yang
Journal: Molecular Biology and Evolution (2023)

Freeze tolerance, the ability of an organism to survive internal ice formation, is a striking survival strategy employed by some ectotherms living in cold environments. However, the genetic bases of this remarkable adaptation are largely unknown. The Amur sleeper (Perccottus glenii), the only known freeze-tolerant fish species, can overwinter with its entire body frozen in ice. Here, we sequenced the chromosome-level genome of the Amur sleeper and performed comparative genomic, transcriptomic, and metabolomic analyses to investigate its strategies for surviving freezing. Evolutionary analysis suggested that the Amur sleeper diverged from its closest non-cold-hardy relative about 15.07 million years ago and has experienced a high rate of protein evolution. Transcriptomic and metabolomic data identified a coordinated and tissue-specific regulation of genes and metabolites involved in hypometabolism, cellular stress response, and cryoprotectant accumulation involved in freezing and thawing. Several genes show evidence of accelerated protein sequence evolution or family size expansion were found as adaptive responses to freezing-induced stresses. Specifically, genetic changes associated with cytoskeleton stability, cryoprotectant synthesis, transmembrane transport, and neuroprotective adaptations were identified as potentially key innovations that aid in freezing survival. Our work provides valuable resources and opportunities to unveil the molecular adaptations supporting freeze tolerance in ectothermic vertebrates.
Smoking as a prognostic factor for survival in patients with disseminated germ cell cancer
Authors: Mikkel Bandak, Kristine Skovly Nielsen, Michael Kreiberg, Thomas Wagner, Josephine Rosenvilde, Charlotta Pisinger, Christoffer Johansen, Gedske Daugaard, Jakob Lauritsen
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract We investigated the impact of smoking on overall survival (OS) in testicular germ cell cancer (TC) patients receiving first-line combination chemotherapy (bleomycin-etoposide-cisplatin [BEP]). Patients who received BEP for metastatic TC were identified in the Danish Testicular Cancer database. Information on smoking status at the time of diagnosis was obtained by medical record review. OS and cause of death were compared between current smokers and never-smokers. Of 1883 eligible patients, information on smoking status was available in 1156 patients, of whom 602 were current smokers. The 10-year OS was 92% in never-smokers compared with 83% in current smokers (P &amp;lt; .001) (hazard ratio for death = 1.85, 95% confidence interval = 1.29 to 2.66, P = .001). A higher proportion of current smokers died of TC compared with nonsmokers (P &amp;lt; .01). Smoking negatively affects survival after BEP in patients with disseminated TC. Vigorous smoking cessation programs are advocated in TC patients.
Polysarcosine-based lipid formulations for intracranial delivery of mRNA
Authors: Dongdong Bi, Dennis Mark Unthan, Lili Hu, Jeroen Bussmann, Katrien Remaut, Matthias Barz, Heyang Zhang
Journal: Journal of Controlled Release (2023)

Messenger RNA (mRNA) is revolutionizing the future of therapeutics in a variety of diseases, including neurological disorders. Lipid formulations have shown to be an effective platform technology for mRNA delivery and are the basis for the approved mRNA vaccines. In many of these lipid formulations, polyethylene glycol (PEG)-functionalized lipid provides steric stabilization and thus plays a key role in improving the stability both ex vivo and in vivo. However, immune responses towards PEGylated lipids may compromise the use of those lipids in some applications (e.g., induction of antigen specific tolerance), or within sensitive tissues (e.g., central nervous system (CNS)). With respect to this issue, polysarcosine (pSar)-based lipopolymers were investigated as an alternative to PEG-lipid in mRNA lipoplexes for controlled intracerebral protein expression in this study. Four polysarcosine-lipids with defined sarcosine average molecular weight (Mn = 2 k, 5 k) and anchor diacyl chain length (m = 14, 18) were synthesized, and incorporated into cationic liposomes. We found that the content, pSar chain length and carbon tail lengths of pSar-lipids govern the transfection efficiency and biodistribution. Increasing carbon diacyl chain length of pSar-lipid led up to 4- and 6-fold lower protein expression in vitro. When the length of either pSar chain or lipid carbon tail increased, the transfection efficiency decreased while the circulation time was prolonged. mRNA lipoplexes containing 2.5% C14-pSar2k resulted in the highest mRNA translation in the brain of zebrafish embryos through intraventricular injection, while C18-pSar2k-liposomes showed a comparable circulation with DSPE-PEG2k-liposomes after systemic administration. To conclude, pSar-lipid enable efficient mRNA delivery, and can substitute PEG-lipids in lipid formulations for controlled protein expression within the CNS.
Conductive polymers and composites-based systems: An incipient stride in drug delivery and therapeutics realm
Authors: G. Kiran Raj, Ekta Singh, Umme Hani, K.V.R.N.S. Ramesh, Sirajunisa Talath, Ankitha Garg, Komal Savadatti, Tanvi Bhatt, K. Madhuchandra, Riyaz Ali M. Osmani
Journal: Journal of Controlled Release (2023)
Single-chain polymer nanoparticles in biomedical applications
Authors: Naomi M. Hamelmann, Jos M.J. Paulusse
Journal: Journal of Controlled Release (2023)

Single-chain polymer nanoparticles (SCNPs) are a well-defined and uniquely sized class of polymer nanoparticles. The advances in polymer science over the past decades have enabled the development of a variety of intramolecular crosslinking systems, leading to particles in the 5–20 nm size regime. Which is aligned with the size regime of proteins and therefore making SCNPs an interesting class of NPs for biomedical applications. The high modularity of SCNP design and the ease of their functionalization have led to growing research interest. In this review, we describe different crosslinking systems, as well as the preparation of functional SCNPs and the variety of biomedical applications that have been explored.
Cooling-induced, localized release of cytotoxic peptides from engineered polymer nanoparticles in living mice for cancer therapy
Authors: Hiroyuki Koide, Kazuhiro Saito, Keiichi Yoshimatsu, Beverly Chou, Yu Hoshino, Sei Yonezawa, Naoto Oku, Tomohiro Asai, Kenneth J. Shea
Journal: Journal of Controlled Release (2023)
Retraction Note: m6A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis
Authors: Dan Jin, Jiwei Guo, Yan Wu, Jing Du, Lijuan Yang, Xiaohong Wang, Weihua Di, Baoguang Hu, Jiajia An, Lingqun Kong, Lei Pan, Guoming Su
Journal: Journal of Hematology & Oncology (2023)
Diabetes in Pregnancy for Mothers and Offspring: Reflection on 30 Years of Clinical and Translational Research: The 2022 Norbert Freinkel Award Lecture
Authors: Anny H. Xiang
Journal: Diabetes Care (2023)

Hyperglycemia during pregnancy is a double-edged sword, affecting both mothers and their offspring and creating a vicious cycle that can affect multiple generations. Research in this field over the past 30 years has greatly improved our understanding of this disease and formed the basis of improved strategies to improve the health of mothers and their babies. Despite this progress, gestational and preexisting diabetes continue to have significant effects on both short- and long-term health of mothers and their offspring. In this article, I provide an overview of the work that my colleagues and I have done to advance the knowledge base around diabetes and pregnancy in four areas: 1) diabetes risk after gestational diabetes mellitus (GDM), including racial and ethnic disparities; 2) the pathophysiology of GDM and subsequent diabetes in Hispanic women; 3) diabetes prevention and β-cell preservation following GDM; and 4) evidence for multiple potential developmental effects in offspring that vary according to the timing of exposure and severity of maternal diabetes during pregnancy. This research continues the legacy of Norbert Freinkel and the concepts that he contributed to the field of diabetes and pregnancy. With the epidemic of obesity, increasing rates of type 1 and type 2 diabetes in youth, and rising prevalence of GDM across all racial and ethnic groups, we have a lot more work to do to combat this disease to break the vicious cycle.
Youth-Onset Type 2 Diabetes: The Epidemiology of an Awakening Epidemic
Authors: Wei Perng, Rebecca Conway, Elizabeth Mayer-Davis, Dana Dabelea
Journal: Diabetes Care (2023)

In this narrative review, we describe the epidemiology (prevalence, incidence, temporal trends, and projections) of type 2 diabetes among children and adolescents (<20 years), focusing on data from the U.S. and reporting global estimates where available. Secondarily, we discuss the clinical course of youth-onset type 2 diabetes, from prediabetes to complications and comorbidities, drawing comparisons with youth type 1 diabetes to highlight the aggressive course of this condition, which, only recently, has become recognized as a pediatric disease by health care providers. Finally, we end with an overview of emerging topics in type 2 diabetes research that have potential to inform strategies for effective preventive action at the community and individual levels.
Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B
Authors: Steven W. Pipe, Frank W.G. Leebeek, Michael Recht, Nigel S. Key, Giancarlo Castaman, Wolfgang Miesbach, Susan Lattimore, Kathelijne Peerlinck, Paul Van der Valk, Michiel Coppens, Peter Kampmann, Karina Meijer, Niamh O’Connell, K. John Pasi, Daniel P. Hart, Rashid Kazmi, Jan Astermark, Cedric R.J.R. Hermans, Robert Klamroth, Richard Lemons, Nathan Visweshwar, Annette von Drygalski, Guy Young, Shelley E. Crary, Miguel Escobar, Esteban Gomez, Rebecca Kruse-Jarres, Doris V. Quon, Emily Symington, Michael Wang, Allison P. Wheeler, Robert Gut, Ying P. Liu, Ricardo E. Dolmetsch, David L. Cooper, Yanyan Li, Brahm Goldstein, Paul E. Monahan
Journal: New England Journal of Medicine (2023)

Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement.
Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson’s Disease
Authors: Vibhor Krishna, Paul S. Fishman, Howard M. Eisenberg, Michael Kaplitt, Gordon Baltuch, Jin Woo Chang, Wei-Chieh Chang, Raul Martinez Fernandez, Marta del Alamo, Casey H. Halpern, Pejman Ghanouni, Roberto Eleopra, Rees Cosgrove, Jorge Guridi, Ryder Gwinn, Pravin Khemani, Andres M. Lozano, Nathan McDannold, Alfonso Fasano, Marius Constantinescu, Ilana Schlesinger, Arif Dalvi, W. Jeff Elias
Journal: New England Journal of Medicine (2023)

Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies.We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months.Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness.Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).
Hemophilia A Gene Therapy — Some Answers, More Questions
Authors: Lindsey A George
Journal: New England Journal of Medicine (2023)

Hemophilia A is an X-linked disorder caused by the loss of coagulation factor VIII function. The phenotype of hemophilia A closely correlates with plasma factor VIII activity and is characterized by spontaneous or trauma-induced bleeding, classically hemarthrosis, that after repeated instances results in disabling hemophilic arthropathy. The current standard care is recurrent intravenous administration of factor VIII or subcutaneous delivery of a bispecific antibody, emicizumab, that mimics some of the functions of activated factor VIII. These therapies convert severe hemophilia A to moderate hemophilia A (characterized by infrequent, spontaneous bleeding) or mild hemophilia A (characterized by bleeding that is typically . . .
Viral Lineages in the 2022 RSV Surge in the United States
Authors: Gordon Adams, Gage K Moreno, Brittany A Petros, Rockib Uddin, Zoe Levine, Ben Kotzen, Katelyn S Messer, Sabrina T Dobbins, Katherine C DeRuff, Christine M Loreth, Taylor Brock-Fisher, Stephen F Schaffner, Sushma Chaluvadi, Sanjat Kanjilal, Jeremy Luban, Al Ozonoff, Daniel J Park, Sarah E Turbett, Katherine J Siddle, Bronwyn L MacInnis, Pardis C Sabeti, Jacob E Lemieux
Journal: New England Journal of Medicine (2023)
The police are perpetrating harm, so why is the government giving them more power?
Authors: Martha Spurrier
Journal: BMJ (2023)

The police are perpetrating harm, so why is the government giving them more power?The police have abused their power, yet the government is giving them even more, writes Martha Spurrier Martha Spurrier director, LibertyThis January, we learned that David Carrick, one of the most prolific sex offenders in UK history, was a serving police officer.He used his position to manipulate and abuse women, including a serving police officer, over a career spanning two decades. 1 This is nothing new, we know Sarah Everard's killer Wayne Couzens used his police badge and handcuffs to abduct her under false pretences before murdering her. 2 Nor is it unusual, with the Metropolitan Police's new chief, Mark Rowley, admitting that two to three serving officers will face court every week for a variety of offences, including domestic and sexual violence.
Selective Photothermal Therapy Based on Lipopolysaccharide Aptamer Functionalized MoS<sub>2</sub> Nanosheet‐Coated Gold Nanorods for Multidrug‐Resistant <i>Pseudomonas aeruginosa</i> Infection
Authors: Jie Lv, Bo Li, Tingting Luo, Chengtao Nie, Weilun Pan, Xiaoxue Ge, Jinsheng Zheng, Yongyu Rui, Lei Zheng
Journal: Advanced Healthcare Materials (2023)

Chronic wounds infected by multidrug-resistant gram-negative bacteria have evolved resistance to traditional antibiotic therapy, posing a threat to global public health in recent years. Herein, a selective therapeutic nanorod (MoS2 -AuNRs-apt) based on molybdenum disulfide (MoS2 ) nanosheets coated gold nanorods (AuNRs) targeting lipopolysaccharide (LPS) is presented. AuNRs have excellent photothermal conversion efficiency in 808 nm laser-guided photothermal therapy (PTT), and the MoS2 nanosheets coating significantly enhances the biocompatibility of AuNRs. Furthermore, the conjugation of the nanorods with aptamer permits active targeting of LPS on the surface of gram-negative bacteria and a specific anti-inflammatory ability in the multidrug-resistant Pseudomonas aeruginosa (MRPA)-infected wound murine model. It is concluded that the antimicrobial effect of these nanorods is considerably more significant than non-targeted PTT. Moreover, they can precisely overcome MRPA bacteria by physical damage and effectively reduce excess M1 inflammatory macrophages to accelerate the healing of infected wounds. Overall, this molecular therapeutic strategy displays great potential as a prospective antimicrobial treatment for MRPA infections.
<i>Alliance for Hippocratic Medicine v. FDA</i> — <i>Dobbs’</i>s Collateral Consequences for Pharmaceutical Regulation
Authors: Patricia J. Zettler, Eli Y. Adashi, I. Glenn Cohen
Journal: New England Journal of Medicine (2023)

A lawsuit contesting the FDA's approval of mifepristone could restrict access to medication abortion by removing the drug from the entire U.S. market.
Evaluation of a Produce Prescription Program for Patients With Diabetes: A Longitudinal Analysis of Glycemic Control
Authors: Kurt Hager, Peilin Shi, Zhongyu Li, Kenneth Chui, Seth A. Berkowitz, Dariush Mozaffarian, Jyoti Chhabra, Joel Wilken, Cunegundo Vergara, Erica Becker, Sara Small, Brent Ling, Sean B. Cash, Sara C. Folta, Fang Fang Zhang
Journal: Diabetes Care (2023)

OBJECTIVE Produce prescriptions have shown promise in improving diabetes care, although most studies have used small samples or lacked controls. Our objective was to evaluate the impacts of a produce prescription program on glycemic control for patients with diabetes. RESEARCH DESIGN AND METHODS Participants included a nonrandom enrollment of 252 patients with diabetes who received a produce prescription and 534 similar control participants from two clinics in Hartford, Connecticut. The start of the COVID-19 pandemic in March 2020 coincided with program implementation. Produce prescription enrollees received vouchers ($60 per month) for 6 months to purchase produce at grocery retail. Controls received usual care. The primary outcome was change in glycated hemoglobin (HbA1c) between treatment and control at 6 months. Secondary outcomes included 6-month changes in systolic (SBP) and diastolic blood pressure (DBP), BMI, hospitalizations, and emergency department admissions. Longitudinal generalized estimating equation models, weighted with propensity score overlap weights, assessed changes in outcomes over time. RESULTS At 6 months, there was no significant difference in change in HbA1c between treatment and control groups, with a difference of 0.13 percentage points (95% CI −0.05, 0.32). No significant difference was observed for change in SBP (3.85 mmHg; −0.12, 7.82), DBP (−0.82 mmHg; −2.42, 0.79), or BMI (−0.22 kg/m2; −1.83, 1.38). Incidence rate ratios for hospitalizations and emergency department visits were 0.54 (0.14, 1.95) and 0.53 (0.06, 4.72), respectively. CONCLUSIONS A 6-month produce prescription program for patients with diabetes, implemented during the onset of the COVID-19 pandemic, was not associated with improved glycemic control.